Fungi are a prominent cause of hospital-acquired infections that are becoming increasingly difficult to control (Pfaller, et al. (2007) Clin Microbiol Rev 20, 133-163). This disturbing trend is driven by the growing number of severely immunocompromised individuals in the population that has occurred as a result of advances in the management of cancer, organ transplantation, autoimmune disorders, and HIV. Most fungus-related morbidity and mortality is caused by the pathogens Candida albicans and Aspergillus fumigatus, which remain costly to treat and extremely difficult to eradicate in the immunocompromised host. Candida species are currently the fourth leading cause of hospital-acquired bloodstream infection and kill up to 40% of their victims, while disseminated Aspergillus infections kill up to 80% of the patients they afflict (Cowen, et al. (2002) Annu Rev Microbiol 56, 139-165; Monk, et al. (2008) Science 321, 367-369).
Fungal pathogens present a particular therapeutic challenge because as eukaryotes, they share many of the same basic molecular mechanisms that support the maintenance and proliferation of mammalian cells. As a consequence, the number of unique exploitable drug targets that have been identified in fungi remains very limited. Only three mechanistically distinct classes of anti-mycotic agents are in widespread clinical use for the treatment of systemic infections. The most widely deployed class, the azoles (e.g., fluconazole), inhibit the cytochrome P450 enzyme 14 α-demethylase. This blocks the conversion of lanosterol to ergosterol, the functional homolog of cholesterol in mammals. Ergosterol is an essential component of the fungal membrane, and the selective fungistatic activity of the azoles results from their disruption of its biosynthesis. Ergosterol itself is the primary target of the oldest class of antifungals, the polyenes (e.g., amphotericin B) which selectively bind this sterol and directly disrupt fungal membrane integrity. The newest class of antifungals, the echinochandins (e.g., caspofungin), inhibits 1, 3 β-glucan synthase. This enzyme mediates an essential step in the production of glucan, the major structural component of the fungal cell wall. Unfortunately, high-grade resistance to all three classes of antifungals occurs frequently in the clinical setting through molecular mechanisms that can involve both target-related mutations and increased transporter-mediated drug efflux. Accordingly, there remains a need to find anti-fungal agents with new targets.